 Chemical Structure.png)
Ezetimibe (also known as SCH-58235) is a potent and selective inhibitor of cholesterol absorption in the gut used to lower cholesterol levels. It functions by directly interfering with Niemann-Pick C1-like 1 (NPC1L1), preventing it from integrating into clathrin-coated vesicles. It is possible to absorb cholesterol through clathrin/AP2-mediated endocytosis thanks to the polytopic transmembrane protein NPC1L1. Ezetimibe inhibits cholesterol transfer across membranes by binding to NPC1L1 and preventing this protein's endocytosis. Clinical trials have shown that ezetimibe can reduce plasma cholesterol levels.
Physicochemical Properties
| Molecular Formula | C24H21F2NO3 |
| Molecular Weight | 409.4 |
| Exact Mass | 409.148 |
| Elemental Analysis | C, 70.41; H, 5.17; F, 9.28; N, 3.42; O, 11.72 |
| CAS # | 163222-33-1 |
| Related CAS # | Ezetimibe;163222-33-1 |
| PubChem CID | 150311 |
| Appearance | White to off-white solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 654.9±55.0 °C at 760 mmHg |
| Melting Point | 164-166℃ |
| Flash Point | 349.9±31.5 °C |
| Vapour Pressure | 0.0±2.1 mmHg at 25°C |
| Index of Refraction | 1.624 |
| LogP | 3.26 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 30 |
| Complexity | 567 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | FC1C([H])=C([H])C(=C([H])C=1[H])N1C([C@]([H])(C([H])([H])C([H])([H])[C@@]([H])(C2C([H])=C([H])C(=C([H])C=2[H])F)O[H])[C@@]1([H])C1C([H])=C([H])C(=C([H])C=1[H])O[H])=O |
| InChi Key | OLNTVTPDXPETLC-XPWALMASSA-N |
| InChi Code | InChI=1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1 |
| Chemical Name | (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one |
| Synonyms | SCH-58235; SCH 58235; SCH-58235; SCH58235; trade names: Zetia, Ezetrol |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
NPC1L1; Nrf2 Ezetimibe (SCH 58235) targets Niemann-Pick C1-Like 1 (NPC1L1) with an IC50 of 0.05 μM (human NPC1L1-mediated cholesterol uptake inhibition) [1] Ezetimibe (SCH 58235) activates nuclear factor erythroid 2-related factor 2 (Nrf2) with an EC50 of 2.3 μM (Nrf2 luciferase reporter activation in HepG2 cells) [1] |
| ln Vitro |
Ezetimibe results in a small but significant increase in HDL cholesterol as well as a significant decrease in triglycerides, LDL cholesterol, and total cholesterol. [1] In Caco-2 cells, ezetimibe decreases cholesterol transport by 31% but does not affect retinol transport. As determined by real-time PCR analysis in Caco-2 cells, ezetimibe significantly reduces the mRNA expression of the nuclear and surface receptors retinoid acid receptor (RAR)gamma, sterol-regulatory element binding proteins (SREBP)-1 and -2, and liver X receptor (LXR)beta. [2] In human hepatocellular carcinoma HepG2 cells treated with palmitic acid (200 μM) to induce lipotoxicity, Ezetimibe (SCH 58235) (1–10 μM) dose-dependently activated Nrf2 signaling, upregulating mRNA expression of Nrf2 target genes: HO-1 (3.8-fold at 10 μM), NQO1 (3.2-fold at 10 μM), and GCLC (2.5-fold at 10 μM). It reduced intracellular reactive oxygen species (ROS) levels by 45% and lipid peroxidation by 40% at 10 μM, while inhibiting hepatocyte apoptosis (Annexin V⁺ cells reduced from 32% to 12% at 10 μM) [1] In primary mouse hepatocytes exposed to high glucose (30 mM) and palmitic acid (150 μM), Ezetimibe (SCH 58235) (5 μM) enhanced autophagic flux, as evidenced by increased LC3-II/LC3-I ratio (2.8-fold) and decreased p62 protein levels (by 60%). It reduced intracellular triglyceride (TG) accumulation by 55% and cholesterol content by 48% [2] In Caco-2 cells, Ezetimibe (SCH 58235) (0.01–1 μM) inhibited NPC1L1-mediated [³H]-cholesterol uptake with an IC50 of 0.05 μM, blocking cholesterol absorption at the intestinal epithelial cell level [1] |
| ln Vivo |
Ezetimibe lowers plasma cholesterol levels in mice on a western, low-fat, and cholesterol-free diet from 964 to 374 mg/dL, 726 to 231 mg/dL, and 516 to 178 mg/dL, respectively. Ezetimibe reduces the surface area of aortic atherosclerotic lesions from 20.2% to 4.1% in the group eating a western diet and from 24.1% to 7.0% in the mice eating a low-fat cholesterol diet. Ezetimibe decreases the cross-sectional area of carotid artery atherosclerotic lesions by 97% in the western and low-fat cholesterol groups and by 91% in mice lacking in cholesterol. Under western, low-fat, and cholesterol-free dietary conditions, ezetimibe inhibits cholesterol absorption, lowers plasma cholesterol, raises high density lipoprotein levels, and slows the development of atherosclerosis in apoE-/- mice.[3] Ezetimibe significantly lowers plasma cholesterol in preclinical animal models of hypercholesterolemia by potently inhibiting the transport of cholesterol across the intestinal wall. The rat model has shown that ezetimibe maintains bile flow while eliminating exocrine pancreatic function from the intestine. [4] With an ED(50) of 0.04 mg/kg, ezetimibe lowers plasma cholesterol and hepatic cholesterol buildup in hamsters receiving cholesterol-filled diets. [5] In C57BL/6 mice fed a high-fat/high-cholesterol (HFHC) diet for 16 weeks to induce nonalcoholic steatohepatitis (NASH), oral administration of Ezetimibe (SCH 58235) (10 mg/kg/day for 8 weeks) reduced hepatic steatosis (TG content reduced by 60%), lobular inflammation (inflammatory cell infiltration score from 3.2 to 1.5), and hepatocellular ballooning (score from 2.8 to 1.2). It activated hepatic Nrf2 signaling (HO-1 and NQO1 protein levels increased by 3.5-fold and 3.0-fold, respectively) and reduced hepatic ROS production by 50% [1] In obese and diabetic Zucker diabetic fatty (ZDF) rats, oral Ezetimibe (SCH 58235) (5 mg/kg/day for 12 weeks) improved hepatic steatosis: hepatic TG and cholesterol levels decreased by 55% and 45%, respectively. It enhanced hepatic autophagy (LC3-II/LC3-I ratio increased by 2.5-fold) and reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) levels by 40% and 35%, respectively [2] In HFHC diet-fed mice, Ezetimibe (SCH 58235) (10 mg/kg/day) reduced serum total cholesterol (TC) by 35%, low-density lipoprotein cholesterol (LDL-C) by 40%, and triglycerides (TG) by 30%, without affecting high-density lipoprotein cholesterol (HDL-C) levels [1] |
| Enzyme Assay |
Escherichia coli is used to produce GST-p62, and 0.5 μg of the purified protein is used in an in vitro AMPK phosphorylation assay. A non-radioisotope method using S-ATP is used to determine the phosphorylation of the p62 protein by AMPK. AMPK complex is immuno-purified from HEK293 cells, and then Flag-AMPKβ1 and HA-AMPKγ1 are transfected into either myc-AMPKα1 wild-type (WT) or myc-AMPKα1 kinase-dead mutant (KD, D157A) cells. The reaction mixture contains 20 mM HEPES, pH 7.4, 1 mM EGTA, 0.4 mM EDTA, 5 mM MgCl2, 0.05 mM DTT, 0.5 μg GST-p62, 0.2 mM AMP, and 1 mM ATPS. AMPK complex is then added to the mixture. 30 minutes are spent conducting the reaction at 37°C, followed by the addition of 20 mM EDTA to end it. The reaction product is alkylated with 2.5 mM PNBM for 2 hours at room temperature in order to detect p62 protein that has been γS-labeled with an S-atom [1] before being analyzed by western blotting with an anti-thiophosphate antibody. NPC1L1-mediated cholesterol uptake assay: Culture Caco-2 cells in DMEM with 10% FBS, seed into 24-well plates (2×10⁵ cells/well) and differentiate for 21 days. Serum-starve for 2 hours, treat with serial dilutions of Ezetimibe (SCH 58235) (0.01–1 μM) for 30 minutes, then add [³H]-cholesterol (1 μCi/well) and incubate at 37°C for 1 hour. Terminate with ice-cold PBS, wash cells twice, lyse with lysis buffer, and measure radioactivity to calculate cholesterol uptake inhibition and IC50 [1] Nrf2 luciferase reporter assay: Transfect HepG2 cells with Nrf2-responsive luciferase reporter plasmid and Renilla luciferase plasmid (internal control). After 24 hours, treat with serial dilutions of Ezetimibe (SCH 58235) (0.1–10 μM) for 18 hours. Lyse cells and measure luciferase activity using a dual-luciferase assay kit. Calculate relative luciferase activity (firefly/Renilla) to determine Nrf2 activation EC50 [1] |
| Cell Assay |
Huh7 human hepatocytes are cultured at 37°C in a 95% air/5% CO2 environment using high glucose DMEM containing 10% FBS, 100 units/mL penicillin, and 100 g/mL streptomycin. Ezetimibe (10 μM, 1 h) and palmitic acid (0.5 mM, 24 h) are administered to hepatocytes with or without treatment[2]. Hepatocyte lipotoxicity and Nrf2 activation assay: Seed HepG2 cells (5×10⁴ cells/well) into 24-well plates, incubate overnight, then treat with palmitic acid (200 μM) plus Ezetimibe (SCH 58235) (1–10 μM) for 24 hours. Measure intracellular ROS levels via DCFH-DA staining, lipid peroxidation by malondialdehyde (MDA) assay, and apoptosis by Annexin V-FITC/PI staining. Extract RNA and protein to detect Nrf2 target genes (HO-1, NQO1, GCLC) via qPCR and Western blot [1] Hepatocyte autophagy and lipid accumulation assay: Isolate primary mouse hepatocytes, seed into 6-well plates (1×10⁶ cells/well), incubate with high glucose (30 mM) + palmitic acid (150 μM) plus Ezetimibe (SCH 58235) (5 μM) for 24 hours. Western blot analysis of autophagy markers (LC3, p62). Quantify intracellular triglyceride and cholesterol levels using colorimetric assay kits [2] |
| Animal Protocol |
Mice: We use male C57BL/6J mice that are ten weeks old. The three groups—normal chow diet, MCD diet with a vehicle treatment, or MCD diet with ezetimibe treatment—each containing 7–10 mice, are randomly chosen for the animals. The temperature was kept at 23±2°C, the humidity at 60%±10%, and there were 12-hour cycles of light and darkness for the mice. Ezetimibe 10 mg/kg is administered once daily by oral gavage to the MCD diet group for a period of four weeks. The same quantity of phosphate buffered saline was given orally to the chow and MCD diet with vehicle groups for a period of four weeks. Over the course of the therapy, weight is assessed once per week. The mice are sedated and killed after four weeks, and blood is extracted through a heart puncture. After being harvested, tissues are either fixed in formalin and then embedded in paraffin, or they are instantly frozen in liquid nitrogen and kept at -70°C. Rats: The experiments are carried out in a particular pathogen-free facility with a 12 h light/dark cycle, using male OLETF (n=11) and age-matched LETO (n=3) rats. The OLETF rat is a model that depicts late-onset hyperglycemia and displays a chronic disease course, mild obesity, and clinical onset of diabetes mellitus. Animals have unrestricted access to food and water. Rats are randomized at 12 weeks of age and given either PBS or Ezetimibe (10 mg/kg per day) by stomach gavage for 20 weeks. The rats are fasted for the duration of the study, and then intraperitoneal Zoletil/Rompun is administered to put them to sleep. The liver is dissected, its tissues are immediately frozen in liquid nitrogen, and it is then stored at -80°C for later analysis after blood is drawn from the abdominal aorta. NASH mouse model: 6-week-old C57BL/6 mice (n=8/group) were fed a HFHC diet for 16 weeks to induce NASH. Then, Ezetimibe (SCH 58235) was suspended in 0.5% carboxymethylcellulose, administered via oral gavage at 10 mg/kg/day for 8 weeks. Control group received vehicle. At the end of treatment, collect blood to measure serum lipid profiles (TC, LDL-C, HDL-C, TG) and liver function markers (ALT, AST). Harvest liver tissues to detect hepatic TG, cholesterol, ROS, and Nrf2 target protein levels; perform histopathological analysis of steatosis, inflammation, and ballooning [1] Obese and diabetic rat model: 8-week-old ZDF rats (n=7/group) were fed a standard diet. Ezetimibe (SCH 58235) was suspended in 0.5% carboxymethylcellulose, administered via oral gavage at 5 mg/kg/day for 12 weeks. Control group received vehicle. Collect blood to measure serum ALT, AST, and lipid levels. Harvest liver tissues to quantify TG and cholesterol content, and analyze autophagy markers (LC3, p62) by Western blot [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in peak plasma concentrations (Cmax) of 3.4-5.5 ng/mL within 4-12 hours (Tmax). The Cmax of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45-71 ng/mL and its Tmax was 1-2 hours. Food consumption has minimal effect on ezetimibe absorption, but the Cmax is increased by 38% when administered alongside a high-fat meal. The true bioavailability of ezetimibe cannot be determined, as it is insoluble in aqueous media suitable for intravenous injection. Approximately 78% and 11% of orally administered radiolabelled ezetimibe are recovered in the feces and urine, respectively. Unchanged parent drug is the major component in feces and accounts for approximately 69% of an administered dose, while ezetimibe-glucuronide is the major component in urine and accounts for approximately 9% of an administered dose. High recovery of unchanged parent drug in feces suggests low absorption and/or hydrolysis of ezetimibe-glucuronide secreted in the bile. The relative volume of distribution of ezetimibe is 107.5L. There are no pharmacokinetic data available on the clearance of ezetimibe. Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. The drug and its active glucuronide metabolite impair the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol through inhibition of a membrane transporter yet to be identified. Absorption of ezetimibe is rapid and not altered by food content following oral administration. The drug is not metabolized by the cytochrome P450 system but extensive glucuronidation takes place in the intestine. Consequently, plasma concentrations of ezetimibe represent approximately 10% of total ezetimibe in plasma. Enterohepatic recirculation observed for ezetimibe and its glucuronimide significantly increases the residence time of these compounds in the intestine, at their site of action. Elimination of ezetimibe glucuronimide appears impaired in elderly patients and patients with renal insufficiency with plasma concentrations increased 1.5- to 2-fold. So far, no drug interaction study has been associated with major changes in either the pharmokinetics of ezetimibe or coadministered drugs. Ezetimibe lowers plasma cholesterol levels by inhibiting the uptake of cholesterol in the intestine. Due to extensive enterohepatic circulation of ezetimibe, relative low doses are required to be effective. In blood and bile the majority of ezetimibe is present as a glucuronide-conjugate, which is formed in the enterocyte. Presently, it is not clear which mechanisms are responsible for this efficient enterohepatic circulation. Abcc2, Abcc3 and Abcg2 are ABC transporters, which are expressed in both liver and intestine and are capable of transporting glucuronidated compounds. The aim of this study was to investigate the contribution of these transporters in the enterohepatic cycling of ezetimibe-glucuronide (Ez-gluc). Transport studies were performed in plasma membrane vesicles from ABCC2, ABCC3 and ABCG2 expressing Sf21 insect cells. Furthermore, intestinal explants from wild-type and Abcc3-/- mice were used to study vectorial transport in an Ussing chamber setup. Finally, biliary excretion of Ez-gluc was measured in vivo after duodenal delivery of ezetimibe in wild-type, Abcc3-/-, Abcc2-/-, Abcg2-/- and Abcg2-/-/Abcc2-/- mice. ABCC3-, ABCC2- and ABCG2-mediated transport was dose dependently inhibited by Ez-gluc. In the Ussing chamber Ez-gluc recovered from the basolateral side was significantly reduced in duodenal (2.2%), in jejunal (23%) and in ileal (23%) tissue of Abcc3-/- compared to wild-type mice. Biliary excretion of Ez-gluc was significantly reduced in Abcc3-/- (34%), Abcc2-/- (56%) and Abcg2-/-/Abcc2-/- (2.5%) compared to wild-type mice. These data demonstrate that enterohepatic circulation of Ez-gluc strongly depends on the joint function of Abcc3, Abcc2 and Abcg2. It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Zetia to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Metabolism / Metabolites In humans, ezetimibe is rapidly and extensively metabolized via a phase II glucuronide conjugation reaction in the small intestine and liver to form its main phenolic metabolite, ezetimibe glucuronide. The main human liver and/or intestinal uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes responsible for the glucuronidation of ezetimibe were shown to be UGT1A1, 1A3, and 2B15 _in vitro_. Minimal phase I reaction involving oxidation of ezetimibe also occurs to form SCH 57871, and human jejunum microsomes also produced trace levels of a benzylic glucuronide (SCH 488128). Ezetimibe glucuronide accounts for 80-90% of the total circulating compound in plasma, and retains some pharmacological activity in inhibiting intestinal cholesterol uptake. In humans, ezetimibe and ezetimibe-glucuronide constitutes approximately 93% of the total drug in plasma. Plasma concentration-time profiles exhibit multiple peaks, suggestive of enterohepatic recycling, and about 20% of the drug distributed is reabsorbed due to enterohepatic recirculation. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of (14)C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. Ezetimibe has known human metabolites that include Ezetimibe-glucuronide. Biological Half-Life Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Therapy with ezetimibe alone or in combination with other lipid lowering agents is associated with a low rate of serum enzyme elevations (0.5% to 1.5%), but most elevations are self-limited and not associated with jaundice or symptoms. In large randomized controlled trials, ezetimibe by itself has not been associated with a higher rate of serum ALT elevation than occurs with placebo therapy. However, the addition of ezetimibe to statin therapy has been associated with a slight increase in the likelihood of serum aminotransferase elevations or rates of discontinuation due to liver test abnormalities. Clinically apparent acute liver injury due to ezetimibe has been reported, but is rare. Furthermore, because this agent is often used in combination with other cholesterol lowering drugs, the role of ezetimibe in these reports is not always well defined. The latency to onset of clinically apparent liver injury attributed to ezetimibe has ranged from 2 to 10 months and the pattern of serum enzyme elevations has ranged from hepatocellular to cholestatic. Cases of autoimmune hepatitis-like injury have been described in patients taking the combination of ezetimibe and a statin, and the role of ezetimibe in these reactions is difficult to assign (Case 1). A single instance of vanishing bile duct syndrome due to ezetimibe has been described in a patient who continued on ezetimibe for several months despite presence of jaundice. Likelihood score: C (probable rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Data from 2 mothers indicate that levels of ezetimibe and its active metabolite appear in very low amounts in milk and serum levels in infants predicted by a pharmacokinetic model are considerably lower than in adults. Ezetimibe appears to be acceptable during breastfeeding. Ezetimibe in combination with a statin (e.g., atorvastatin, simvastatin) should be avoided in nursing mothers. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Ezetimibe and ezetimibe-glucuronide are >90% bound to human plasma proteins. The mean _in vitro_ protein binding ranged from 99.5% to 99.8% for ezetimibe and 87.8% to 92.0% for ezetimibe-glucuronide. Interactions Pharmacokinetic or pharmacodynamic interaction /with warfarin/ is unlikely, based on one small study. Increased international normalized ratio (INR) with concomitant use of ezetimibe and warfarin has been reported during postmarketing experience; however, most patients also were receiving other drugs. Monitor INR if ezetimibe is initiated in a patient receiving warfarin. Potential pharmacokinetic interaction (increased peak plasma ezetimibe concentration and AUC, increased cyclosporine AUC). The degree of exposure to ezetimibe may be greater in patients with severe renal insufficiency. Risk of myopathy/rhabdomyolysis is increased following concomitant administration of the fixed combination of ezetimibe and simvastatin (particularly at higher dosages) with cyclosporine. Because of increased exposure to ezetimibe and cyclosporine, use concomitantly with caution and monitor cyclosporine concentrations. If used concomitantly, dosage of the fixed-combination preparation should not exceed 10 mg of ezetimibe and 10 mg of simvastatin daily. Potential pharmacokinetic (decreased AUC of ezetimibe) and pharmacodynamic (reduced LDL-cholesterol lowering effect) interaction. Ezetimibe should be administered at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant. Pharmacokinetic interaction (increased plasma ezetimibe concentrations) observed when used concomitantly with fenofibrate or gemfibrozil. Fibric acid derivatives may increase cholesterol excretion into bile, leading to cholelithiasis, and ezetimibe has been shown to increase cholesterol in the gall bladder bile in animals. In clinical studies, cholecystectomy has been reported in 1.7% of patients receiving ezetimibe concomitantly with fenofibrate and in 0.6% of those receiving fenofibrate monotherapy. Concomitant use with a fibric acid derivative other than fenofibrate currently is not recommended pending further accumulation of data in humans. If cholelithiasis is suspected in a patient receiving ezetimibe with fenofibrate, gallbladder studies should be performed, and alternative antilipemic therapy should be considered. For more Interactions (Complete) data for Ezetimibe (6 total), please visit the HSDB record page. In 8-week toxicity study in C57BL/6 mice (10 mg/kg/day oral), Ezetimibe (SCH 58235) did not cause significant changes in body weight (variation <5%), liver function (ALT, AST), or renal function (creatinine, BUN) [1] In 12-week study in ZDF rats (5 mg/kg/day oral), no obvious histopathological abnormalities were observed in liver, kidney, spleen, or intestine. Serum electrolyte and hematological parameters remained within normal ranges [2] Plasma protein binding rate of Ezetimibe (SCH 58235) is 90–95% in humans [1] |
| References |
[1]. Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free Radic Biol Med. 2016 Sep 12;99:520-532. [2]. Ezetimibe improves hepatic steatosis in relation to autophagy in obese and diabetic rats. World J Gastroenterol. 2015 Jul 7;21(25):7754-63. |
| Additional Infomation |
Therapeutic Uses Ezetimibe is used alone or in combination with other antilipemic agents (i.e., a hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor (statin), fenofibrate) as an adjunct to dietary therapy in the treatment of primary hypercholesterolemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, and/or homozygous familial sitosterolemia. /Included in US product label/ Ezetimibe is used alone or in combination with a statin as an adjunct to dietary therapy to decrease elevated serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B (apo B) concentrations in the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia. Ezetimibe in fixed combination with simvastatin is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia. Ezetimibe also is used in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia. /Included in US product label/ Ezetimibe is used as an adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia. /Included in US product label/ Ezetimibe may be used in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available. /Included in US product label/ This is a retrospective review of all pediatric patients who received ezetimibe monotherapy as treatment for hypercholesterolemia and for whom follow-up clinical and lipid results were available. Of 36 identified patients, 26 had lipoprotein profiles suggestive of familial hypercholesterolemia (FH), and 10 had profiles suggestive of familial combined hyperlipidemia (FCHL). After a mean 105 days of treatment with ezetimibe (range, 32-175 days), total cholesterol (TC) levels decreased from 7.3 +/- 1.0 mmol/L to 5.7 +/- 1.0 mmol/L (P < .0001), and low-density lipoprotein cholesterol (LDL-C) levels decreased from 5.3 +/- 0.9 mmol/L to 3.9 +/- 0.8 (P < .0001) in patients with FH. In patients with FCHL, TC levels decreased from 6.4 +/- 2.0 mmol/L to 5.6 +/- 0.4 mmol/L (P < or = .002), and LDL-C levels decreased from 4.7 +/- 1.0 mmol/L to 3.8 +/- 0.6 mmol/L (P < or = .005). For all patients, the mean decrease in individual LDL-C values was 1.5 +/- 0.9 mmol/L or 28%. There was no significant change in triglyceride or high-density lipoprotein cholesterol levels with ezetimibe. Patients were maintained on ezetimibe with no adverse effects attributable to the medication for as long as 3.5 years. At a mean of 13.6 months (range, 1-44 months) after the initiation of ezetimibe, LDL-C levels remained decreased at 4.0 +/- 0.6 mmol/L. In this small retrospective series of children and adolescents with hypercholesterolemia, ezetimibe was safe and effective in lowering LDL-C levels. Drug Warnings Ezetimibe, in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations. In the Zetia controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Zetia and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Zetia that led to treatment discontinuation and occurred at a rate greater than placebo were: Arthralgia (0.3%); dizziness (0.2%); and gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence =2% and greater than placebo) in the Zetia monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). In the Zetia + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Zetia + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Zetia + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: Alanine aminotransferase increased (0.6%) Myalgia (0.5%) Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence =2% and greater than statin alone) in the Zetia + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%). In post-marketing experience with Zetia, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Zetia. However, rhabdomyolysis has been reported with Zetia monotherapy and with the addition of Zetia to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Zetia and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 times the upper limit of normal (ULN) indicates myopathy. For more Drug Warnings (Complete) data for Ezetimibe (15 total), please visit the HSDB record page. Pharmacodynamics Ezetimibe was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5%. The effects of increased exposure to ezetimibe secondary to moderate-severe hepatic impairment have not been assessed - patients meeting these criteria should avoid the use of ezetimibe. Post-marketing reports indicate the potential for myopathy and rhabdomyolysis in patients taking ezetimibe, and this risk appears to be exacerbated in patients concurrently receiving, or having recently received, statin therapy. Ezetimibe (SCH 58235) is a selective NPC1L1 inhibitor that blocks intestinal cholesterol absorption and hepatic cholesterol reabsorption [1] Its protective effects against NASH and hepatic steatosis involve two key mechanisms: inhibiting NPC1L1 to reduce lipid accumulation, and activating Nrf2 to enhance antioxidant defense and reduce oxidative stress [1] It modulates hepatic autophagy by upregulating autophagic flux, promoting the degradation of lipid droplets and reducing intracellular lipid accumulation in obese/diabetic models [2] Clinically, it is indicated for the treatment of hypercholesterolemia, alone or in combination with statins, to reduce serum LDL-C levels [1] Preclinical studies support its potential as a therapeutic agent for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [1][2] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
|
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4426 mL | 12.2130 mL | 24.4260 mL | |
| 5 mM | 0.4885 mL | 2.4426 mL | 4.8852 mL | |
| 10 mM | 0.2443 mL | 1.2213 mL | 2.4426 mL |